The Organic Chemistry of Drug Synthesis

The corresponding analogue 4 in which the amine is protected as atert-butyloxycarbonyl function t-BOC comprises the starting material forthe HIV protease inhibitor amprenavir 12.. The t-

THE ORGANIC

CHEMISTRY OF DRUG SYNTHESIS

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Wiley Bicentennial Logo: Richard J Pacifico

Library of Congress Cataloging-in-publication Data is available.

ISBN 978-0-470-10750-8

Printed in the United States of America

To the memory of I Moyer Hunsberger and Melvin S Newman

who set me on course

1 Peptidomimetic Compounds / 2

A Antiviral Protease Inhibitors / 2

1 Human Immunodeficiency Virus / 2

C Miscellaneous Monocyclic Compounds / 29

2 Polycyclic Compounds: Steroids / 31

A 19-Nor Steroids / 31

B Corticosteroid Related Compounds / 34

vii

3 Compounds Related to Aniline / 50

4 Compounds Related to Arylsulfonic

1 Compounds with One Heteroatom / 83

2 Compounds with Two Heteroatoms / 91

A Oxazole and Isoxazoles / 91

B Imidazoles and a Pyrrazole / 94

2 Compounds with Two Heteroatoms / 121

A Pyrimidines / 121

B Miscellaneous Six-Membered Heterocycles / 133

References / 136

7 FIVE-MEMBERED HETEROCYCLES FUSED TO

1 Compounds with One Heteroatom / 139

8 SIX-MEMBERED HETEROCYCLES FUSED TO

1 Compounds with One Heteroatom / 163

A Benzopyrans / 163

B Quinolines and Their Derivatives / 167

C Quinolone Antibacterial Agents / 172

2 Compounds with Two Heteroatoms / 176

A Benzoxazines / 176

B Quinazolines / 178

C Miscellaneous Benzo-Fused Heterocycles / 184

References / 186

1 Compounds with Five-Membered Rings Fused

to Six-Membered Rings / 189

A Compounds with Two Heteroatoms / 189

B Compounds with Three Heteroatoms / 191

C Compounds with Four Heteroatoms / 195

2 Compounds with Two Fused Six-Membered Rings / 208

3 Miscellaneous Compounds with Two Fused

Heterocyclic Rings: Beta Lactams / 213

References / 215

1 Compounds with Three Fused Rings / 217

2 Compounds with Four Fused Rings / 228

3 Compounds with Five or More Fused Rings:

1976 What had been conceived as a single book at this point became aseries The roughly 200 new USAN coined every five years over thenext few decades turned out to nicely fit a new volume in the series.This then dictated the frequency for issuing new compendia After themost recent book in the series, Volume 6, was published in 1999, itbecame apparent that a real decline in the number of new drug entitiesassigned non-proprietary names had set in The customary half-decadeinterval between books was apparently no longer appropriate.

A detailed examination of the 2005 edition of the USAN Dictionary ofDrug Names turned up 220 new non-proprietary names that had beenassigned since the appearance of Volume 6 Many of these compoundsrepresent quite novel structural types first identified by sophisticated new

xi

cell-based assays This clearly indicated the need for the present volume inthe series The Organic Chemistry of Drug Synthesis.

This new book follows the same format as the preceding volumes.Compounds are classed by their chemical structures rather than by theirbiological activities This is occasionally awkward since compoundswith the same biological activity but significantly different structures arerelegated to different chapters, a circumstance particularly evident withestrogen antagonists that appear in three different chapters The crossindex found at the end of the book, it is hoped, partly overcomes thisproblem The syntheses are discussed from an organic chemist’s point ofview, accompanied by the liberal use of flow diagrams As was the case

in the preceding volumes, a thumbnail explanation of the biological activity

of each new compound precedes the discussion of its biological activity.Several trends in the direction of drug discovery research seemed toemerge during the preparation of this book Most of the preceding volumesincluded one or more therapeutic classes populated by many structurallyrelated potential drugs Volume 6 for example described no fewer than ahalf dozen HIV-protease inhibitors and a similar number of the “triptan”drugs aimed at treating migraine The distribution of therapeutic activities

in the present volume is quite distinct from that found in the earlier books.This new set, for example, includes a sizeable number of antineoplastic andantiviral agents These two categories together in fact account for just overone third of the compounds in the present volume The antitumor candi-dates are further distinct in that specific agents act against very specifictumor-related biological end points This circumstance combined withmechanism based design in other disease areas probably reflect the wide-spread adoption of in-vitro screening in the majority of pharmaceuticalresearch laboratories

The use of combinatorial chemistry for generating libraries to feedin-vitro screens has also become very prevalent over the past decade.This book is silent on that topic since compounds are only includedwhen in a quite advanced developmental stage Some of the structuresthat include strings of unlikely moieties suggest that those compoundsmay have been originally prepared by some combinatorial process.The internet has played a major role in finding the articles and patentsthat were required to put this account together The NIH-based websitePubChem was an essential resource for finding structures of compoundsthat appear in this book; hits more often than not include CAS RegistryNumbers References to papers on the synthesis of compounds couldsometimes be found with the other NIH source PubMed The ubiquitousGoogle was also quite helpful for finding sources for syntheses In some

of the earlier volumes, references to patents were accompanied by ences to the corresponding CAS abstract since it was often difficult toaccess patents The availability of actual images of all patents fromeither the U.S patent office (www.uspto.gov) or those from Europeanelsewhere (http://ep.espacenet.com) has turned the situation around.There was always the rather pricey STN online when all else failed.This volume, like its predecessors, is aimed at practicing medicinal andorganic chemists as well as graduate and advanced undergraduate students

refer-in organic and medicrefer-inal chemistry The book assumes a good workrefer-ingknowledge of synthetic organic chemistry and some exposure to modernbiology

As a final note, I would like to express my appreciation to the staff of thelibrary in Building 10 of the National Institutes of Health Not only werethey friendly and courteous but they went overboard in fulfilling requeststhat went well beyond their job descriptions

PREFACE xiii

CHAPTER 1

OPEN-CHAIN COMPOUNDS

Carbocyclic or heterocyclic ring systems comprise the core of chemicalstructures of the vast majority of therapeutic agents This finding results

in the majority of drugs exerting their effect by their actions at receptor

or receptor-like sites on cells, enzymes, or related entities These actions depend on the receiving site being presented with a moleculethat has a well-defined shape, distribution of electron density, and array

inter-of ionic or ionizable sites, which complement features on the receptor.These requirements are readily met by the relatively rigid carbocyclic orheterocyclic molecules A number of important drugs cannot, however,

be assigned to one of those structural categories Most of these agentsact as false substrates for enzymes that handle peptides The central struc-tural feature of these compounds is an open-chain sequence that mimics acorresponding feature in the normal peptide Although these drugs oftencontain carbocyclic or heterocyclic rings in their structures, these featuresare peripheral to their mode of action Chapter 1 concludes with a fewcompounds that act by miscellany and mechanisms and whose structures

do not fit other classifications

The Organic Chemistry of Drug Synthesis, Volume 7 By Daniel Lednicer

Copyright # 2008 John Wiley & Sons, Inc.

1

1 PEPTIDOMIMETIC COMPOUNDS

A Antiviral Protease Inhibitors

1 Human Immunodeficiency Virus The recognition of acquiredimmune deficiency syndrome (AIDS) in the early 1980s and the subsequentexplosion of what had seemed at first to be a relatively rare disease into amajor worldwide epidemic, lent renewed emphasis to the study of virus-caused disease Treatment of viral disease is made particularly difficult

by the fact that the causative organism, the virion, does not in the exactmeaning of the word, replicate Instead, it captures the reproductivemechanism of infected cells and causes those to produce more virions.Antiviral therapy thus relies on seeking out processes that are vital for pro-ducing those new infective particles The first drugs for treating humanimmunodeficiency virus (HIV) infection comprised heterocyclic basesthat interfered with viral replication by interrupting the transcription ofviral ribonucleic acid (RNA) into the deoxyribonucleic acid (DNA)required by the host cell for production of new virions The relativelyfast development of viral strains resistant to these compounds has proven

to be a major drawback to the use of these reverse transcriptase inhibitors.The drugs do, however, still form an important constituent in the so-calledcocktails used to treat AIDS patients Some current reverse transcriptaseinhibitors are described in Chapters 4 and 6 The intense focus on theHIV virus revealed yet another point at which the disease may betackled Like most viruses, HIV comprises a packet of genetic material,

in this case RNA, encased in a protein coat This protein coat providesnot only protection from the environment, but also includes peptides thatrecognize features on host cells that cause the virion to bind to the celland a few enzymes crucial for replication Many normal physiologicalpeptides are often elaborated as a part of a much larger protein.Specialized peptidase enzymes are required to cut out the relevantprotein This proved to be the case with the peptides required forforming the envelopes for newly generated virions Compounds thatinhibit the scission of the protein elaborated by the infected host, theHIV protease inhibitors, have provided a valuable set of drugs for treatment

of infected patients The synthesis of four of those drugs were outlined inVolume 6 of this series Work on compounds in this class has continuedapace as evidenced by the half dozen new protease inhibitors that havebeen granted nonproprietary names since then

As noted in Volume 6, the development of these agents was greatlyfacilitated by a discovery in a seemingly unrelated area Research aimed

at development of renin inhibitors as potential antihypertensive agents hadled to the discovery of compounds that blocked the action of this peptidecleaving enzyme The amino acid sequence cleaved by renin was found

to be fortuitously the same as that required to produce the HIV peptidecoat Structure – activity studies on renin inhibitors proved to be of greatvalue for developing HIV protease inhibitors Incorporation of an aminoalcohol moiety proved crucial to inhibitory activity for many of theseagents This unit is closely related to the one found in the statine, anunusual amino acid that forms part of the pepstatin, a fermentationproduct that inhibits protease enzymes

This moiety may be viewed as a carbon analogue of the transition state

in peptide cleavage The fragment is apparently close enough in structure

to such an intermediate as to fit the cleavage site in peptidase enzymes.Once bound, this inactivates the enzyme as it lacks the scissile carbon –nitrogen bond All five newer HIV protease inhibitors incorporate thisstructural unit

One scheme for preparing a key intermediate for incorporating thatfragment begins with the chloromethyl ketone (1) derived from phenyl-alanine, in which the amine is protected as a carbobenzyloxy (Cbz)group Reduction of the carbonyl group by means of borohydrideaffords a mixture of aminoalcohols The major syn isomer 2 is then iso-lated Treatment of 2 with base leads to internal displacement of halogenand formation of the epoxide (3).1

1 PEPTIDOMIMETIC COMPOUNDS 3

The corresponding analogue (4) in which the amine is protected as atert-butyloxycarbonyl function (t-BOC) comprises the starting material forthe HIV protease inhibitor amprenavir (12) Reaction of 4 withisobutyl amine leads to ring opening of the oxirane and formation of theaminoalcohol (5) The thus-formed secondary amine in the product isconverted to the sulfonamide (6) by exposure to p-nitrobenzenesulfonyl chlor-ide The t-BOC protecting group is then removed by exposure to acid leading

to the primary amine (10) In a convergent scheme, chiral hydrofuran (8) is allowed to react with bis(N-succinimidooxy)carbonate (7).The hydroxyl displaces one of the N-hydroxysuccinimide groups to affordthe tetrahydrofuran (THF) derivative (9) equipped with a highly activatedleaving group Reaction of this intermediate with amine 10 leads to displace-ment of the remaining N-hydroxysuccinimide and incorporation of thetetrahydrofuryl moiety as a urethane (11) Reduction of the nitro group thenaffords the protease inhibitor (12).2

3-hydroxytetra-Much the same sequence leads to a protease inhibitor that incorporates asomewhat more complex furyl function-linked oxygen heterocyclic Thisfused bis(tetrahydrofuryl) alcohol (16) was designed to better interactwith a pocket on the viral protease The first step in preparing this inter-mediate consists of reaction of dihydrofuran (13) with propargyl alcoholand iodosuccinimide to afford the iodoether (14) Free radical dis-placement of the iodine catalyzed by cobaloxime leads to the fused

perhydrofuranofuran (15) The exomethylene group in the product is thencleaved by means of ozone; reductive workup of the ozonide leads toracemic 16 The optically pure single entity (17) is then obtained by resol-ution of the initial mixture of isomers with immobilized lipase.3

That product (17) is then converted to the activated N-hydoxysuccinimidederivative 18 as in the case of the monocyclic furan Reaction withthe primary amine 10 used to prepare amprenavir then leads to the urethane(19) Reduction of the nitro group then affords darunavir4(20)

The synthesis of the amprenavir derivative, which is equipped with asolubilizing phosphate group, takes a slightly different course from thatused for the prototype The protected intermediate 5 used in the synthesis

of 12 is allowed to react with benzyloxycarbonyl chloride to provide the

1 PEPTIDOMIMETIC COMPOUNDS 5

doubly protected derivative 21, a compound that bears a t-BOC group

on one nitrogen and a Cbz grouping on the other Exposure to acidserves to remove the t-BOC group, affording the primary amine 22 Thiscompound is then condensed with the activated intermediate 9 used inthe preparation of the prototype to yield the urethane 23 Catalytichydrogenation then removes the remaining protecting group to givethe secondary amine 24 Reaction as before with p-nitrobenzenesulfonylchloride gives the sulfonamide 25 This intermediate is allowed toreact with phosphorus oxychloride under carefully controlled conditions.Treatment with aqueous acid followed by a second catalytic hydrogenationaffords the water soluble protease inhibitor fosamprenavir (26).5

The preceding three antiviral agents tend to differ form each other byonly relatively small structural details The next protease inhibitor includessome significant structural differences though it shares a similar centralaminoalcohol sequence that is presumably responsible for its activity.Construction of one end of the molecule begins with protection of thecarbonyl function in p-bromobenzaldehyde (27) as its methyl acetal (28)

by treatment with methanol in the presence of acid Reaction of that mediate with the Grignard reagent from 4-bromopyridine leads to unusual

inter-displacement of bromine from the protected benzaldehyde and formation

of the coupling product Mild aqueous acid restores the aldehyde function

to afford 29 This compound is then condensed with carbethoxy hydrazine

to form the respective hydrazone; reduction of the imine function leads tothe substituted hydrazine (30) Reaction of 30 with the by-now familiaramino-epoxide (4) results in oxirane opening by attack of the basic nitro-gen in the hydrazine (30) and consequent formation of the addition product

31 The t-BOC protecting group is then removed by treatment withacid The final step comprises acylation of the free primary amine in 32with the acid chloride from the O-methyl urethane (33) This last com-pound (32) is a protected version of an unnatural a-aminoacid that can

be viewed as valine in with an additional methyl group on what hadbeen the side-chain secondary carbon atom Thus, the protease inhibitoratazanavir(34) is obtained.6

A terminal cyclic urea derivative of valine is present at one terminus

in lopinavir (43) Preparation of this heterocyclic moiety begins with version of valine (35) to its phenoxycarbonyl derivative by reaction withthe corresponding acid chloride Alkylation of the amide nitrogen with3-chloropropylamine in the presence of base under very carefully con-trolled pH results in displacement of the phenoxide group to give the

con-1 PEPTIDOMIMETIC COMPOUNDS 7

urea intermediate (37) This compound then spontaneously undergoesinternal displacement of chlorine to form the desired derivative (38).

The statine-like aminoalcohol function in this compound differs fromprevious examples by the presence of an additional pendant benzylgroup; the supporting carbon chain is of necessity longer by onemember Condensation of that diamine (39),7 protected at one end as itsN,N-dibenzyl derivative, with 2,6-dimethylphenoxyacetic acid (40) givesthe corresponding amide (41) Hydrogenolysis then removes the benzylprotecting groups to afford primary amine 42 Condensation of that withintermediate 34 affords the HIV protease inhibitor 43.8

2 Human Rhinovirus Human rhinoviruses are one of the most quent causes of that affliction that accompanies cooling weather, thecommon cold This virus also consists of a small strand of RNA enveloped

fre-in a peptide coat Expression of fresh virions fre-in this case depends on vision of the proper peptide by the infected host cell That in turn hinges onexcision of that peptide from the larger initially produced protein Proteaseinhibitors have thus been investigated as drugs for treating rhinovirusinfections The statine-based HIV drugs act by occupying the scissionsite of the protease enzyme and consequently preventing access by theHIV-related substrate That binding is, however, reversible in the absence

pro-of the formation pro-of a covalent bond between drug and enzyme A differentstrategy was employed in the research that led to the rhinovirus proteaseinhibitor rupinavir (58) The molecule as a whole is again designed to fitthe protease enzyme, as in the case of the anti-HIV compounds In contrast

to the latter compound, however, this agent incorporates a moiety that willform a covalent bond with the enzyme, in effect inactivating it with finality.The evocative term “suicide inhibitor” has sometimes been used for thisapproach since both the substrate and drug are destroyed

The main part of the somewhat lengthy convergent synthesis consists ofthe construction of the fragment that will form the covalent bond with theenzyme The unsaturated ester in this moiety was designed to act as aMichael acceptor for a thiol group on a cysteine residue known to bepresent at the active site The preparation of that key fragment starts withthe protected form of chiral 3-amino-4-hydroxybutyric acid (44); notethat the oxazolidine protecting group simply comprises a cyclic hemi-aminal of the aminoalcohol with acetone The first step involves incorpor-ation of a chiral auxiliary to guide introduction of an additional carbonatom The carboxylic acid is thus converted to the corresponding acidchloride and that reacted with the (S)-isomer of the by-now classic oxazo-lidinone (45) to give derivative 46 Alkylation of the enolate from 46 withallyl iodide gives the corresponding allyl derivative (47) as a single enan-tiomer The double bond is then cleaved with ozone; reductive workup ofthe ozonide affords the aldehyde (48) Reductive amination of the carbonylgroup with 2,6-dimethoxybenzylamine in the presence of cyanoboro-hydride proceeds to the corresponding amine 49 This last step in effectintroduced a protected primary amino group at that position The chiralauxiliary grouping is next removed by mild hydrolysis The initiallyformed amino acid (50) then cyclizes to give the five-membered lactam(51) Treatment under stronger hydrolytic conditions subsequently serves

to open the cyclic hemiaminal grouping to reveal the free aminoalcohol

1 PEPTIDOMIMETIC COMPOUNDS 9

(52) Swern-type oxidation of the terminal hydroxyl group in this last mediate affords an intermediate (53) that now incorporates the aldehydegroup required for building the Michael acceptor function Thus reaction

inter-of that compound with the ylide from ethyl 2-diethoxyphosphonoacetateadds two carbon atoms and yields the acrylic ester (54)

The remaining portion of the molecule is prepared by the condensation

of N-carbobenzyloxyleucine with p-fluorophenylalanine to yield theprotected dipeptide (55) Condensation of that intermediate with theMichael acceptor fragment (54) under standard peptide-forming conditionsleads to the tripeptide-like compound (53) Reaction of 53 with dichloro-dicyanoquinone (DDQ) leads to unmasking of the primary amino group

at the end of the chain by oxidative loss of the DMB protecting group.Acylation of that function with isoxazole (55) finally affords the rhinovirusprotease inhibitor rupinavir (58).9

2 MISCELLANEOUS PEPTIDOMIMETIC COMPOUNDS

Polymers of the peptide tubulin make up the microtubules that form themicroskeleton of cells Additionally, during cell division these filamentspull apart the nascent newly formed pair of nuclei Compounds that interferewith tubulin function and thus block this process have provided some valu-able antitumor compounds The vinca alkaloid drugs vincristine and vinblas-tine, for example, block the self-assembly of tubulin into those filaments.Paclitaxel, more familiarly known as Taxol, interestingly stabilizes tubulinand in effect freezes cells into mid-division Screening of marine naturalproducts uncovered the cytotoxic tripeptide-like compound hemiasterlin,which owed its activity to inhibition of tubulin A synthetic programbased on that lead led to the identification of taltobulin (69), an antitumorcompound composed, like its model, of sterically crowded aminoacid ana-logues The presence of the nucleophile-accepting acrylate moiety recalls 58.One arm of the convergent synthesis begins with the construction of thatacrylate-containing moiety Thus, condensation of the t-BOC protecteda-aminoaldehyde derived from valine with the carbethoxymethylene phos-porane (60) gives the corresponding chain extended amino ester (61).Exposure to acid serves to remove the protecting group to reveal theprimary amine (62) Condensation of that intermediate with the tertiarybutyl-substituted aminoacid 33, used in a previous example leads to theprotected amide (63); the t-BOC group in this is again removed withacid unmasking the primary amino group in 64 Construction of theother major fragment first involves addition of a pair of methyl groups

2 MISCELLANEOUS PEPTIDOMIMETIC COMPOUNDS 11

to the benzylic position of pyruvate (65) This transform is accomplishedunder surprisingly mild conditions by simply treating the ketoacid withmethyl iodide in the presence of hydroxide Treatment of product 66with methylamine and diborane results in reductive amination of thecarbonyl group, and thus formation of a-aminoacid 67 as a mixture ofthe two isomers Condensation of that with the dipeptide-like moiety 64under standard peptide-forming conditions gives the amide 68 as amixture of diastereomers The isomers are then separated by chromato-graphy; saponification of the terminal ester function of the desired (SSS)-isomer affords the antitumor agent taltobulin (69).10

The alkylating agent cyclophosphamide is one of the oldest U.S Foodand Drug Administration (FDA)-approved antitumor agents, having been

in use in the clinic for well over four decades Though this peutic agent is reasonably effective, it is not very selective The drugaffects many sites and is thus very poorly tolerated Over the years, therehas been much research devoted to devising more site-selective relatedcompounds It was established that a heterocyclic ring in this compound

chemothera-is opened metabolically and then dchemothera-iscarded The active alkylating olite comprises the relatively small molecule commonly known as the

metab-“phosphoramide mustard”

This result opens the possibility of delivering this active fragment or arelated alkylating function in a large molecule that would itself be recog-nized by an enzyme involved in cancer progression As an example, itwas observed that many types of cancer tissues often have elevatedlevels of glutathione transferase, the agent that removes glutathione Aversion of the modified natural substrate, glutathione, which carries aphosphoramide alkylating function, has shown activity on variouscancers Reaction of bromoethanol with phosphorus oxychloride affordsintermediate 70 This compound reacts without purification with bis-2-chloroethylamine to give the phosphoramide (71), which is equippedwith two sets of alkylating groups Compound 71 is then reacted withthe glutathione analogue 72, in which phenylglycine replaces the glycineresidue normally at that position The bromine atom in intermediate 71

is apparently sufficiently more reactive than the chlorines in the mustards

so that displacement by sulfur preferentially proceeds to 73 Oxidation ofthe sulfide with hydrogen peroxide affords canfosfamide (74).11,12

The D(R) isomer of the amino acid N-methyl-D-aspartate, more monly known as NMDA serves as the endogenous agonist at a number

com-of central nervous system (CNS) receptor sites This agent is not onlyinvolved in neurotransmission, but also modulates responses elicited byother neurochemicals A relatively simple peptide-like molecule hasbeen found to act as an antagonist at NMDA receptors This activity ismanifested in vivo as antiepileptic activity This agent in addition blocksthe nerve pain suffered by many diabetics, which is often called neuro-pathic pain The synthesis begins by protecting the unnatural D-serine

2 MISCELLANEOUS PEPTIDOMIMETIC COMPOUNDS 13

(75) as its carbobenzyloxy derivative 76 This is accomplished by reacting

75 with the corresponding acid chloride Reaction of the productwith methyl iodide in the presence of silver oxide alkylates both thefree hydroxyl and the carboxylic acid to give the ether ester (77).Saponification followed by coupling with benzylamine leads to the benzy-lamide (78) Hydrogenolysis of the Cbz protecting group (79) followed

by acylation with acetic anhydride affords lacosamide (80).13

As noted in the discussion of canfosfamide, alkylating agents have a longhistory as a class of compounds used in chemotherapy The trend is to attachthe active electrophillic groups to molecules that will deliver them to specificsites A simple alkylating agent, cloretazine (83), is being actively pursuedbecause of its promising antitumor activity Exhaustive methanesulfonation

of hydroxyethyl hydrazine with methanesulfonyl chloride yields the trimesylate (81) Reaction of this intermediate with lithium chloride leads todisplacement of the O-mesylate by chlorine and formation of the alkylatinggroup in 82 Treatment of 82 with the notorious methylisocyanate (MCI)yields the antitumor agent cloretazine (83).14,15

N,N,O-The relatively simple homologue of taurine, 3-aminosulfonic acid(84a), also known as homotaurine, is an antagonist of the neurochemicalgamma-aminobutyric acid (GABA) Homotaurine has been found to sup-press alcoholism in various animal models Speculation is that this occursbecause of its activity against GABA to which it bears a some resemblance.The calcium salt (84b) of the N-acetyl derivative has been used to helpalcoholics maintain abstinence from alcohol by preventing relapse Thecompound is prepared straightforwardly by acylation of homotaurine inthe presence of calcium hydroxide and acetic anhydride.16 The product,acamprosate calcium (84b), was approved by FDA for use in the UnitedStates in 2004.

A relatively simple derivative of phenylalanine shows hypoglycemicactivity This compound, nateglinide, is usually prescribed for use as anadjunct to either metformin, or one of the thiazolidine hypoglycemicagents Catalytic reduction of the benzoic acid (85) leads to the correspond-ing substituted cyclohexane as a mixture of isomers This compound is thenesterified with methanol to give the methyl esters (86) Treatment withsodium hydride leads 86 to equilibrate to the more stable trans isomer 87via its enolate Condensation of 87 with the ester of phenylalanine (88)yields nateglinide (89) after saponifications.17

The hypoglycemic agent repaglinide may loosely be classed as a omimetic agent, because it essentially shows the same activity as nateglinide.The actual synthetic route is difficult to decipher from the patent in which it

peptid-2 MISCELLANEOUS PEPTIDOMIMETIC COMPOUNDS 15

is described No description is provided for the origin of the startingmaterials It is speculated that condensation of the protected monobenzylester (90) with diamine 91 would lead to the amide (92) Hydrogenolysis

of the benzyl ester in the product would afford the free acid Thus, nide (93) would be obtained.18

repagli-Formation of blood clots is the natural process that preserves the integrity

of the circulatory system Damage to the vasculature sets off an intricatecascade of reactions These reactions culminate in the formation of a fibrinclot that seals the damaged area preventing the further loss of blood.Surgery, heart attacks, and other traumatic events lead to inappropriateformation of clots that can result in injury by blocking the blood supply

to organs and other vital centers The drugs that have traditionally beenused to prevent formation of clots, coumadin and heparin have a verynarrow therapeutic ratio, necessitating close monitoring of blood levels ofthese drugs in patients One of the first steps in the formation of a clotinvolves the binding of fibrinogen to specific receptors on the plateletsthat start the process A number of fibrinogen inhibitors have recentlybeen developed whose structure is based on the sequence of amino acids

in the natural product Two more recent compounds, melagartan, andxymelagartan, both contain the amidine (or guanidine) groups that areintended to mimic the similar function in fibrinogen and that characterizethis class of drugs.19

The synthesis of these agents begins with the hydrogenation of glycine t-BOC amide (94) to the corresponding cyclohexyl derivative 95.The free carboxyl group is then coupled with the azetidine (96) to afford

phenyl-the amide (97) Saponification with lithium hydroxide yields phenyl-the free acid(98) The carboxyl group in that product is then coupled with thebenzylamine (99), where the amidine group at the para position is protected

as the benzyloxycarbonyl derivative to give intermediate 100 Theprotecting group on the terminal amino group is then removed byhydrolysis with acid (101) The primary amine in this last intermediate isthen alkylated with benzyl bromoacetate Hydrogenolysis removes theprotecting groups on the terminal functions in this molecule to affordmelagartan (102).20

Intermediate 100 serves as the starting material for the structurallyclosely related fibrinogen inhibitor xymelagartan Hydrogenation overpalladium on charcoal removes the protecting group on the amidinefunction (103) This compound is then allowed to react with what is

in effect and unusual complex ester of carbonic acid (104) The basicnitrogen on the amidine displaces nitrophenol, a good leaving group

to afford 106 Regiochemistry is probably dictated by the greater basicity

of the amidine group compared to the primary amine at the other end

of the molecule The amine is then alkylated with the sulfonyl derivative of ethyl hydroxyacetate Reaction of this last inter-mediate (107) with hydroxylamine result in an exchange of thesubstitutent on the amidine nitrogen to form an N-hydroxyamidine.Thus, xymelagartan (108) is obtained.20 This drug is interestinglyrapidly converted to 102 soon after ingestion and is in effect simply aprodrug for the latter

trifluoromethyl-2 MISCELLANEOUS PEPTIDOMIMETIC COMPOUNDS 17

Drugs that inhibit the conversion of angiotensin 1 to the stricting angiotensin 2, the so-called angiotensin converting enzyme(ACE) inhibitors, block the action of angiotensin converting enzyme,one of a series of zinc metalloproteases A closely related enzymecauses the degradation of the vasodilating atrial natriuretic peptide Acompound that blocks both metalloproteases should in principle lowervascular resistance and thus blood pressure by complementary mechan-isms A drug that combines those actions, based on a fused two-ringheterocyclic nucleus, omapatrilat, is described in Chapter 10 A relatedcompound that incorporates a single azepinone ring shows much thesame activity The synthesis begins by Swern oxidation of the terminalalcohol in the heptanoic ester 109 Reaction of the product 110 with tri-methylaluminum proceeds exclusively at the aldehyde to afford themethyl addition product (111) A second Swern oxidation, flowed thistime by methyl titanium chloride, adds a second methyl group toafford the gem-dimethyl derivative (112) Construction of the azepinonering begins by replacement of the tertiary carbinol in 112 with an azidegroup by reaction with trimethylsilyl azide and boron trifluoride.Hydrogenation of the product (113) reduces the azide to a primaryamine and at the same time cleaves the benzyl ester to the correspondingacid (114) Treatment of this intermediate with a diimide leads to for-mation of an amide, and thus the desired azepinone ring (115) The

vasocon-phthalimido function, which has remained intact through the precedingsequence, is now cleaved in the usual way by reaction with hydrazine.The newly freed amine is again protected, this time as it triphenylmethylderivative The anion on the amide nitrogen from treatment of 116 withlithium hexamethyl disilazane is then alkylated with ethylbromoacetate;exposure to trifluoracetic acid (TFA) then cleaves the protecting group

on the other nitrogen to afford 117 The primary amino group isacylated with (S)acetylthiocinnamic acid (118) Saponification cleavesboth the acetyl protection group on sulfur and the side-chain ethylester to afford gemopatrilat (119).21

REFERENCES

1 D.P Getman et al., J Med Chem 36, 288 (1993)

2 R.D Tung, M.A Murcko, G.R Bhisetti, U.S Patent 5,558,397 (1996) Thescheme shown here is partly based on that used to prepare darunavir andphosamprenavir due to difficulty in deciphering the patent

3 A.K Ghosh, Y Chen, Tetrahedron Lett 36, 505 (1995)

4 D.L.N.G Surleraux et al., J Med Chem 48, 1813 (2005)

5 L.A Sobrera, L Martin, J Castaner, Drugs Future, 23, 22 (2001)

6 G Bold et al., J Med Chem 41, 3387 (1998).

7 For a scheme for this intermediate see D Lednicer,“The Organic Chemistry ofDrug Synthesis”, Vol 6, John Wiley & Sons, Inc., NY 1999, pp 12,13

8 E.J Stoner et al., Org Process Res Dev 4, 264 (2000)

9 P.S Dragovich et al., J Med Chem 42, 1213 (1999)

10 A Zask et al., J Med Chem 47, 4774 (2004)

11 L.M Kauvar, M.H Lyttle, A Satyam, U.S Patent 5,556,942 (1996)

12 A Satyam, M.D Hocker, K.A Kane-Maguire, A.S Morgan, H.O Villar,M.H Lyttle, J Med Chem 39, 1736 (1996)

13 J.A McIntyre, J Castaner, Drugs Future 29, 992 (2004)

14 A Sartorelli, K Shyam, U.S Patent 4,684,747 (1987)

15 A Sartorelli, K Shyam, P.G Penketh, U.S Patent 5,637,619 (1997)

16 J.P Durlach, U.S Patent 4,355,043 (1982)

17 S Toyoshima, Y Seto, U.S Patent, 4,816,484 (1989)

18 W Grell, R Hurnaus, G Griss, R Sauter, M Reiffen, E Rupprecht, U.S.Patent, 5,216,167 (1993)

19 See Ref 7, pp 15–18

20 L.A Sobrera, J Castaner, Drugs Future, 27, 201 (2002)

21 J.A Robl et al., J Med Chem 42, 305 (1999)

CHAPTER 2

ALICYCLIC COMPOUNDS

The slimness of this chapter very aptly reflects the importance of aromaticand heterocyclic moieties as cores for therapeutic agents This sectionincludes several agents that depend on the presence of on a single alicyclicgroup for their activity Though a few of the compounds included in thischapter do include a benzene ring, that group does not seem to play amajor role in their biological activity Sizeable chapters were devoted inthe earlier volumes in this series to the discussion of drugs based on thesteroid nucleus This area, in common with the prostaglandins that openthis chapter, has received relatively little attention in recent years Ahandful of steroids thus round out this section

1 MONOCYCLIC COMPOUNDS

A Prostaglandins

The discovery of the prostaglandins in the mid-1960s led to an enormousamount of research in both industrial and academic laboratories.1Much ofthis work was arguably based on the mistaken premise that these hormone-like compounds would provide the basis for the design of major newclasses of therapeutic agents Analogy with the large number of important

The Organic Chemistry of Drug Synthesis, Volume 7 By Daniel Lednicer

Copyright # 2008 John Wiley & Sons, Inc.

21

drugs that had emerged from manipulation of the structure of the steroidhormones provided at least some of the impetus for research on the pros-taglandins The expectation of major classes of new drugs was to someextent dispelled by the findings in the late 1960s that prostaglandins andother products derived from arachidonic acid tended to mediate injuriousresponses, such as inflammation rather than hormonal effects In spite ofthis, several compounds based on this structure have found uses in theclinic These include, for example, misoprostol, a drug based on the ben-eficial effect of this class of compounds on the mucous lining of thestomach This compound differs from the naturally occurring prostaglandin

E (PGE) by the removal of the side chain hydroxyl to one carbon furthestfrom the cyclopentane and presence of an additional methyl group on thatposition Other compounds based on this structure provide several ophthal-mic products These topical prostaglandins are used to lower intraocularpressure in glaucoma patients They are believed to cause the outflow

of fluid within the eye by binding to specific intraocular receptors Thesecompounds are classed as PGFs Since both ring oxygens comprisealcohols

glau-to the condensation product of the ylide with the aldehyde The trans

stereochemistry of the newly formed olefin follows from the normal course

of this reaction Reduction of the side-chain carbonyl group with zinc ohydride gives the alcohol 5 after separation of the isomers Reaction withmild base results in hydrolysis of the diphenyl ester protecting group (6).The newly revealed alcohol, as well as that on the side chain, are then pro-tected as their tetrahydropyranyl ethers by reaction with dihydropyran inthe presence of acid (7) Controlled reduction of the lactone ring with dii-sobutylaluminum hydride (DIBAL-H) stops at the lactol stage (8).Condensation with the zwitterionic salt-free ylide, 4-triphenylphosphino-butyrate, results in condensation with the open aldehyde form of thelactol The “salt free” conditions of this reaction account for theformation of the new olefin with cis stereochemistry The acid is thenconverted to its isopropyl ester by reaction of the carboxylate salt withisopropyl iodide There is thus obtained travaprost (9).2

bor-O

CF 3

1

(CH 3 O) 2 POCH 3 BuLi

2

O O

H 3 C

O

CH=O O

O O

P

O

O O

7

DIBAL-H O

O H

THPO

O

CF 3 OTHP

1 MONOCYCLIC COMPOUNDS 23